title: Bis-pyranobenzoquinones as a new family of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in mammalian cells and the protozoan parasite Leishmania.
abstract: We have synthesized a set of bis-pyranobenzoquinones through a direct and highly efficient approach based on a double intramolecular domino Knoevenagel hetero Diels-Alder reaction. These bis-pyranobenzoquinone derivatives are compounds whose skeletons have similarities to those of some anticancerous and leishmanicidal drugs. Considering that these drugs are substrates for some members of the ATP-binding cassette (ABC) family of proteins that confers a multidrug resistance (MDR) phenotype, we have carried out the biological evaluation of 20 bis-pyranobenzoquinones as modulators of the MDR phenotype in mammalian cell lines overexpressing P-glycoprotein, MRP1, or BCRP. Moreover, we also tested some of these compounds as potential MDR modulators in a Leishmania tropica line overexpressing a P-glycoprotein-like transporter. Compounds 9 and 10 are, in this work, the most promising reversal agents of MDR in human cancer cell lines, while compounds 4 and 20 showed potent reversal activity of MDR phenotype in the protozoan parasite Leishmania.
authors.affiliation: Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, 38206, La Laguna,Tenerife, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jiménez-Alonso
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Pérez-Lomas
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz Martinez
authors.forename: Haydee
authors.initials: H
authors.lastname: Chávez Orellana
authors.forename: Angel G
authors.initials: AG
authors.lastname: Ravelo
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Matías
authors.initials: M
authors.lastname: López
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003630:Daunorubicin; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D007895:Leishmania tropica / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D021261:Parasitic Sensitivity Tests; D010641:Phenotype; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016227:Benzoquinones; D003630:Daunorubicin